The objectives are to determine in vivo the relative bioavailabilities and bioconversion of four cyclic prodrugs of RGD-peptidomimetics using a dog model and to determine their in vitro and ex vivo antithrombotic activities. Two prodrugs of each of two linear RGD-peptidomimetics currently on the market or in late stage development as intravenous products will be synthesized using two distinct linker technologies. Based on the results of these studies, a lead candidate will be identified for potential commercial development as an oral antithrombotic agent. There has been tremendous progress in the development of RGD- peptidomimetic derived antithrombotic agents. Administration of these agents is limited to intravenous routes due to poor oral bioavailability resulting from physicochemical properties unfavorable to cell membrane permeation. The low membrane permeation of RGD- peptidomimetics results from their size, charge, solubility, hydrogen- bonding potential, enzymatic stability and conformation. The cyclic prodrugs change these properties to increase their ability to permeate membranes. The prodrugs transiently mask the charge and hydrogen- bonding potential, improve the enzymatic stability and induce folding of the molecule to form a compact structure. After crossing the intestinal mucosa, the cyclic prodrugs are hydrolyzed by esterase to release the parent compound, which is then available to elicit its pharmacological action. PROPOSED COMMERCIAL APPLICATIONS: All currently marketed RGD-peptide based antithrombic agents are administered via intravenous injection. The success of this research will enable the development of a new class of orally active antithrombic agents for cardiovascular disease management. With the data provided by the in vivo studies proposed, ProQuest intends to actively market the rights to license and practice the cyclic peptide technology to multiple pharmaceutical and biotechnology companies for antithrombic and other indications.